Heat Shock Proteins (HSP)

These constitute a large family of immunomodulatory agents [67]. Their traditional function is to serve as protein-folding chaperones, and as hallmarks of exosomes, being found in nearly all proteomic studies of MP, especially HSP-70. Several appear to have neuron-specific functions. For example, antibodies to HSP-90beta interfered with remyelination [68].

The small HSP, alphaB crystallin, elevations of which are associated with a range of inflammatory neurodegenerative disease, was shown to be secreted in exosomes [69], as discussed also by vanNoort [67]. Pinocytic uptake of exosomes has been found to depend on an HSP called ERK1/ERK2 (HSP27) [70].

MP as Immune Complex (IC) and Complement

Several neuroinflammatory disorders are known or suspected to involve autoimmunity. Practically all proteomic studies of MP/exosomes detect substantial amounts of IgG, IgM, and complement (C) fragments on MP. It has long been known that MP-associated antibody-antigen (Ab:Ag) complexes (IC) are released on MP by the action of C. Recently, it was shown that MP-IC exert significant neuroinflammatory action [42]. The cause of shedding of IC from cell surfaces is often C-mediated attack on the opsonized cells, resulting in the release of Ab/Ag/C complex MP. A specific protein, mortalin, has been identified as instrumental in this process [71]. Mortalin belongs to the HSP family (“stress chaperones”) and has been implicated in Parkinson’s disease (PD) [72]. Additional related references are given in the review by Robbins et al. [73], covering also cytokines on MP and their surface expression of PAMPs/DAMPs (“pathogen-associated molecular patterns” and “danger-associated molecular patterns”), which should include also “altered-self” proteins. The C system plays versatile roles in neuroinflammation, including beneficial ones [74].

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